Kerry Hildreth, MD is a geriatrician and instructor in the Division of Geriatric Medicine. Her research focuses on the role of cardiovascular risk factors in cognitive impairment. Her past research has investigated the mechanistic role of insulin resistance in cognitive impairment, and more recently the effects of sex hormones on peripheral vascular function. This proposed project integrates these areas by investigating vascular mechanisms underlying the effects of loss of ovarian function on cognition in women. The candidate's immediate goals are to strengthen existing research and professional skills, and to develop new skills in areas in which she has not yet received significant training. The research and career development plan are designed to launch the candidate's career toward her long-term goal of becoming a successful independent investigator in clinical aging research, and a leader in the area of cardiovascular risk and cognitive impairment. Career Development Plan. The key elements of the research career development plan are: 1) strengthening current and developing new research and professional skills; 2) regular ongoing interactions with a strong, established mentoring team; and 3) structured activities (e.g. formal coursework, conferences and seminars). Environment,. Dr. Hildreth will be working in an outstanding Environment, with strong institutional support, state- of-the-art research facilities, and an impressive track record in transitioning junior investigators into successful independent researchers. The candidate's mentor and co-mentor are established, funded scientists who have successfully mentored numerous junior investigators. The candidate will also have support from three consulting mentors with recognized expertise in their respective areas of research. The candidate will have access to the resources of the institution's Clinical Translational Sciences Award (CTSA) and Clinical Translational Research Center (CTRC), as well as the Institute of Cognitive Science. Research. This project will investigate vascular dysfunction as a potential mechanism for the effects of loss of ovarian function on cognition. The study will be done in conjunction with Dr. Kohrt's Females, Aging, Metabolism and Exercise study in which women nearing menopause are randomized to 6 months of ovarian hormone suppression with gonadotropin releasing hormone agonist (GnRHa), or placebo. We will measure vascular (arterial stiffness and endothelial function) and cognitive (prefrontal cortex (PFC) activation by fMRI) at baseline and 6 months. A subgroup of GnRHa-treated subjects will complete an additional 3 months of GnRHa with estradiol (E2) add-back with testing at 9 months. We hypothesize that GnRHa treatment will be associated with significant declines in vascular and cognitive function, that these declines will be restored with E2, and that changes in PFC activation will be associated with changes in vascular function. Results will add to knowledge about vascular contributions to cognitive impairment and generate preliminary data for future intervention studies to prevent or delay cognitive decline.